The broad objectives are to determine the mechanisms by which: a) fatty acid and lipoprotein (LP) synthesis are regulated in the liver cell and b) membrane lipid synthesis is regulated and coupled to the control of macromolecular biosyntheses (RNA, DNA, and protein) in E. coli. Hyperlipidemia characterized by elevated plasma LP levels is a risk factor for cardiovascular disease. Since the liver is the major contributor of LP's to the circulation, it is proposed that hyperlipoproteinemias can result from aberrantly-regulated hepatic LP synthesis and secretion. Because of its enormous output of LP, particularly when estrogen-activated, the avian liver cell will be used (in vitro, in vivo, and as source of purified regulatory enzymes, e.g. acetyl CoA carboxylase) as model system to determine: 1) short- and long-term points and mechanisms of enzymatic control of very-low density lipoprotein (VLDL) synthesis, b) to what extent and how "feeder" pathways (fatty acid, triglyceride, phospholipid, cholesterol, apoVLDL(s)) of VLDL synthesis are coordinated, c) the mechanism(s) by which estrogen stimulates VLDL synthesis, and d) the regulatory properties of acetyl CoA carboxylase and certain "early enzymes" of cholesterogenesis. Ongoing studies will be extended on the mechanism of: a) the "stringent" control of membrane lipid synthesis and acetyl CoA carboxylase mediated by the pleiotropic effector, (p)ppGpp, and b) the rapid curtailment of stable RNA synthesis induced by the shut-down of membrane lipid synthesis. BIBLIOGRAPHIC REFERENCES: Lane, M. Daniel, Moss, Joel, and Polakis, S. E. (1975) Acetyl Co-enzyme A Carboxylase, in Sub-Unit Enzyme: Biochemistry and Function, Ed. by K. Ebner, Marcel Dekker, Inc., New York., Chapt. 5, p. 181-221. Clinkenbeard, K. D., and Reed, W. D., Mooney, R. A., and Lane, M. D., (1975) Intracellular Localization of the 3-Hydroxy-3-Methylglutaryl CoA Cycle Enzymes in Liver: Separate Cytoplasmic and Mitochondrial 3-Hydroxy-3-Methylglutaryl CoA Generating Systems for Cholesterogenesis and Ketogenesis, J. Biol. Chem., 250, 3108.